PROJECT SUMMARY It has long been thought that thoracic aortic dissections result from blood entering the aortic wall through an ?intimal flap? and separating the intramural layers. There is no direct evidence for this concept, however. This proposal offers a new paradigm for understanding aortic dissection. It is motivated by (i) serendipitous in vitro observations of load-induced intramural delaminations within the thoracic aorta of two different mouse models that also exhibit dramatic aortic dissections in vivo and (ii) our recent theoretical / computational advances that offer, for the first time, a mechanically mechanistic explanation for the initiation of an aortic delamination (separation of wall layers) that can progress to a dissection (separation with intramural blood). Specifically, we observed spontaneous intramural delaminations, without an intimal flap, during in vitro biaxial testing of otherwise grossly normal appearing aorta that were excised from ApoE-/- mice that were infused for 4 days with a high dose of angiotensin-II and from mice having a conditional knockout of the transforming growth factor type 2 receptor. These observations are the first, to our knowledge, of an intramural delamination as it develops under physiologic loading in a vessel having a native geometry, noting that we have never seen such in vitro delaminations in literally hundreds of experiments on arteries from mice that do not dissect in vivo. Both our novel observations and our new computational results point to an intramural swelling process (i.e., Donnan pressure) that conspires with local intramural stress concentrations to initially separate intramural layers and then to propagate this damage into what could become an aortic dissection in vivo. We will combine our in vitro methods for quantifying spontaneous delamination with three novel computational models to quantify the underlying mechanical mechanism of failure, driven mainly by a high tensile radial stress that separates the layers. The primary goal of this 2-year R21 project is, therefore, to elucidate the mechanical mechanisms by which a compromised thoracic aorta delaminates under physiologic loads (i.e., cyclic pressurization at the in vivo value of axial stretch). This work is significant because of the high mortality associated with aortic dissection and its prevalence in young and old individuals alike. This work builds on a strong foundation that we have built over the past two years via the development of novel computational models (finite element and continuum-particle), yet it is highly innovative because of the fortuitous discovery in vitro of spontaneous intramural delaminations in two mouse models that are prone to dissection in vivo and which promise to provide unique structural and mechanical data for model refinement and validation.